CLINICS 2013;68(10):1318-1324
A cytopathological and immunohistochemistry study Russ HH et al.
administration of a topical beta-blocker; sinus bradycardia, second-degree or third-degree atrioventricular block, sinoatrial block, overt cardiac failure, or cardiogenic shock that would preclude the safe administration of a topical betablocker; or a severe medical or psychiatric condition were also excluded from the study. A prospective, randomized, single-blind, multicenter, parallel group, interventional study was conducted between March 2009 and September 2010 at the Federal University of Sa˜o Paulo (UNIFESP) in Sa˜o Paulo, Brazil. The participants were allocated to each treatment group following the sequence of a randomization table. The randomization table was generated using software (Stata, version 11, College Station, Texas, USA) and a block size of three. The participants were enrolled and assigned to each group by the study coordinator. After the sample size was calculated, 33 patients were selected (11 patients were randomly distributed into three different groups according to medication regimen) by two examiners (HR and NL) and were allocated using permuted-block randomization (block size = 3; allocation rate 1:1:1) into the following three groups, independently of age, sex or residence: latanoprost+timolol (LT); bimatoprost+timolol (BT); or travoprost+timolol (TT) (Figure 1). The medications were administered once daily in the evening for 12 weeks in selected patients in all of the groups. The clinical data collected included the patients’ demographic data (age, sex and ethnicity). All of the patients underwent routine ophthalmological examinations prior to and after three months of treatment. The ocular surface evaluation included biomicroscopic examination of the lids, conjunctiva, cornea and tear film. The diagnostic tests included Schirmer’s test with anesthesia, Lissamine green vital staining, tear film break-up time (TBUT) and impression cytology. The OSDI questionnaire was also applied. After the ocular surface evaluation, intraocular pressure (IOP) was measured with the Goldmann applanation tonometer. The patients were examined at two centers (Graefe Institute of Ophthalmology and Brasilia Base Hospital), following instructions provided by the Cornea and External Disease Service in the Department of Ophthalmology, UNIFESP. All of the IOP measurements were obtained at the same time (8 a.m.). The rooms where the examinations were performed had neither air conditioning nor windows, and the air humidity and temperature were controlled with specific equipment. Prior to the examination, the patients rested for 20 minutes with the door to the room closed. The tests were performed by two researchers (HR and NL) and were analyzed at the Ocular Surface Advanced Center (CASO) by two blinded investigators (JB and PANF). Those investigators who assessed the primary outcomes of the study were blinded to the allocation status of the participants. The statistician who performed the data analysis was blinded to all information. Dry eye was defined as a TBUT score of ,5 seconds (2% fluorescein, Ophthalmos, Sa˜o Paulo, SP, Brazil), ,5 mm wetting in the Schirmer’s test (Schirmer strips, Ophthalmos, Sa˜o Paulo, SP, Brazil) with topical anesthesia (0.5% proxymetacaine chlorohydrate, AnestalconH, Alcon Laborato´rios do Brasil, Sa˜o Paulo, SP, Brazil) and corneal and conjunctival
While the systemic side effects induced by topical PG analogues are rare, iris hyperpigmentation, excessive eyelash growth and conjunctival hyperemia have been reported among the local side effects caused by these drugs (3-5). Conditions suggestive of the stimulation or reactivation of ocular inflammatory responses, such as anterior uveitis or cystoid macular edema, have also been associated with the use of PG analogues (6). Ocular surface dysfunction has also been related to glaucoma treatment. Beta-blockers have been known to induce conjunctival hyperemia, punctate keratitis and corneal anesthesia, as well as dry eye and allergic blepharoconjunctivitis (7-9). Previous studies with patients who received long-term treatment with topical medications showed that both hypotensive drugs and their preservatives (especially benzalkonium chloride – BAK) could increase the number of inflammatory cells and fibroblasts in the substantia propria of the conjunctiva and reduce the number of goblet cells, thereby inducing ocular surface changes manifested clinically as dry eye (8-11). The length of administration, concentration and amount of these drugs have been related to the severity of the side effects. In addition, there has been strong evidence suggesting that these changes might increase the risk of trabeculectomy failure (12,13). However, most of the information on this subject was published prior to the introduction of PG analogues. The purpose of this study was to evaluate (clinically, histologically and via immunocytochemistry) the ocular surface changes induced by glaucoma treatment with topical FCs of PG analogues and timolol.
& MATERIALS AND METHODS Inclusion criteria Eligible patients were adults ($18 years of age) with a clinical diagnosis of primary open-angle glaucoma (POAG) or ocular hypertension (OH) in at least one eye and with no previous topical hypotensive treatment. The selected patients had a open iridocorneal angle upon gonioscopy examination. POAG was diagnosed on the basis of characteristic optic disc changes and/or glaucomatous visual field loss demonstrated on the Humphrey visual field analyzer (HFA) (Humphrey Instruments, Inc., Zeiss Humphrey, San Leandro, California, USA). IOP, measured at 8 a.m., had to be between 26 mm Hg and 35 mm Hg in the study eye(s). In addition, patients were required to have a corrected distance visual acuity (CDVA) of 20/70 or better in each eye, and those with glaucoma had to have a recent (within three months) visual field examination showing a mean deviation greater than -15 dB and no fixation threat. Finally, the eligible patients were required to be able to follow instructions, to be willing and able to attend all of the study visits, and to provide informed consent prior to screening.
Exclusion criteria Patients were excluded if they met any of the following criteria: previous ocular surgery; active ocular inflammation; or clinically diagnosed dry eye. Patients with hypersensitivity or poor tolerance to any components of the study medication; with bronchial asthma or history of bronchial asthma; with bronchial hyperreactivity or severe chronic obstructive pulmonary disease that would preclude the safe
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